The use of urokinase in medicine as an activator of plasminogen is well known, since it possesses well pronounced thrombolytic properties. Urokinase is employed in treatment of such diseases as pulmonary thromboembolism, thrombosis of deep veins, diseases of brain vessels and myocardial infarction. However the therapy by means of native urokinase is complicated due to its inactivation under the effect of blood inhibitors and endogenous proteases, as well as due to the impossibility of maintaining a high local content of the preparation in the injured organ. In the urokinase treatment, it is necessary to repeatedly administer high doses of the preparation. These difficulties can be surmounted through combining of the enzymes with high-molecular carriers. The enzyme derivatives possess an increased stability or resistance in respect of various inactivation factors; they also feature a delayed withdrawal from the organism.
Derivatives of urokinase combined with high-molecular carriers and methods for preparing the same are known. Thus, urokinase is combined with sepharose-4B (cf. Wiman B., Wallen P. Eur.J.Biochem., 35, 25, 1973) using activation of the carrier with cyanogen bromide. The use of such a highly toxic compound for medical purposes is impossible.
Also known is a method for preparing urokinase derivatives, wherein urokinase is "sewn-in" into the polyacrylamide gel (Capet. Antanini F. L., Tamenasse J., Can.J.Biochem., 53, 890, 1975) after treatment thereof with sodium nitrite in an acidic medium, the thus-diazotized carrier being reacted with the enzyme through azo-coupling. In this manner a water-insoluble urokinase derivative is obtained which, however, also cannot be employed in medicine.
Water-soluble heat-resistant urokinase derivatives possessing thrombolytic activity have not been hitherto described in the literature.